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Abstract

We present the case of an 11-year-old boy presenting with haemoptysis, dyspnoea and
weight loss as a manifestation of isolated pulmonary vasculitis, leading to pulmonary
hypertension. He also appeared to have a longstanding dural venous sinus thrombosis.
This rare presentation, especially in childhood, might represent a case of the seldomly
reported Hughes-Stovin syndrome. The patient achieved remission after therapy with
cyclophosphamide pulses and high-dose steroids. Based on the presented case and review
of the literature, we propose that this syndrome might be a variant of polyarteritis
nodosa. This report highlights diagnostic issues and describes a successful treatment
regimen.

Background

According to the EULAR/PRINTO/PReS consensus criteria vasculitis of childhood is classified
as small, medium-sized or large vessel vasculitis, or 'other' [1]. In childhood, pulmonary involvement is most frequently observed in vasculitis which
preferentially affects small vessels, such as Wegener's granulomatosis, microscopic
polyangiitis and Churg-Strauss syndrome. Pulmonary involvement is seldomly observed
in large and medium vessel vasculitis, such as Takayasu arteritis, Kawasaki disease
and polyarteritis nodosa (PAN) [1-3]. An exception is Behçet's disease (BD), in which the formation of pulmonary artery
aneurysms occurs in 1-8% of adult BD patients. Similar rates have been found in pediatric
case series [2,4-6].

In this report we describe an eleven-year-old boy suffering from pulmonary medium
sized vessel vasculitis, combined with dural venous sinus thrombosis. We highlight
the difficulty in establishing a definite diagnosis in the context of current diagnostic
criteria and discuss Hughes-Stovin syndrome (HSS) as a potential diagnosis. HSS is
characterized by the combination of multiple bilateral pulmonary artery aneurysms
and venous thrombosis, and has been suggested to be an incomplete variant of BD [5,7]. We will review pediatric cases of HSS from the literature and discuss the possibility
that it is rather a variant of PAN with specific pulmonary involvement, based on its
clinical manifestations in relation to current diagnostic guidelines and its therapeutic
response.

Case Presentation

An 11-year-old boy was admitted to our hospital with cough, fatigue, and weight loss
(~4 kg) of 4 months duration, and hemoptysis starting the day before admission. The
past medical history was unremarkable. His mother was Spanish, his father Dutch. The
family medical history was negative for autoinflammatory or autoimmune diseases.

A bronchoscopy with transbronchial biopsy and bronchial alveolar lavage was performed.
The biopsy results were not consistent with malignancy or sarcoidosis but were not
conclusive. Therefore, a cervical mediastinoscopy was performed, and histological
examination of the enlarged lymph node revealed no signs of malignancy, tuberculosis
or sarcoidosis, but a reactive pattern with numerous lymphocytes, lymphoblasts and
plasma cells. Culture of sputum, blood, stomach contents, bronchoalveolar lavage fluid
and serology could not identify an infectious cause explaining the reactive lymphadenopathy.

Evaluation by an ophthalmologist for autoimmune related eye disease showed bilateral
papilledema. There were no further symptoms of a raised intracranial pressure. Magnetic
resonance imaging of the cerebrum showed dural venous sinus thrombosis with extensive
collateral vessel formation (Figure 1A). Six weeks after admission, the patient again developed hemoptysis. Physical examination
now revealed a cardiac murmur, due to tricuspid regurgitation, and a loud second heart
sound, suggesting pulmonary hypertension. This was confirmed by cardiac catheterization.
The mean pressure in the left pulmonary artery was 30 mmHg, the pulmonary wedge pressure
was 13 mmHg, the cardiac index was 2 l/min/m2, and the pulmonary resistance measured 8.4 resistant units per m2, thus indicating moderate pulmonary hypertension. Angiography and CT-angiography
showed multiple aneurysms in the medium sized arteries (pulmonary artery, Figure 1B). The abdominal, cervical and coronary arteries were also investigated by angiography
and appeared unaffected. The performance of an open lung biopsy was considered too
risky because of the patient's clinical condition.

Under the working diagnosis of medium-sized vessel vasculitis with moderate pulmonary
hypertension as a consequence, the patient was treated with intravenous gamma globulin
(2 g/kg) for two days, intravenous prednisolone (35 mg/day) and cyclophosphamide (750
mg/m2, once per month, 12 pulses), sildenafil (40 mg/day) and bosentan (125 mg/day). Anticoagulation
therapy was initiated in the acute phase but stopped after one week. Ten days thereafter
the patient developed recurrent hemoptysis.

Twenty-five days after initiation of the anti-inflammatory treatment, the ESR returned
to the normal range; however, after five weeks the patient developed massive bleeding
in his respiratory tract. The aneurysmal right bronchial artery was identified as
the focus of the bleeding by digital substraction angiography and embolized with microspheres.
The patient required mechanical ventilation and was treated in the intensive care
unit for three weeks. After ten weeks he was sufficiently recovered to be discharged.
The exercise tolerance was severely decreased but improved gradually as demonstrated
by the results of the 6 minutes walk test. Seven weeks after embolization, the walked
distance was 178 meters; eighteen months later this had improved to 442 meters. However,
the walked distance is still below reported results from healthy age-matched males
[8].

After the final cyclophosphamide pulse azathioprine was started (2 mg/kg/day, for
2 years). Steroids were tapered gradually and discontinued 18 months after initiation
of therapy. No important side effects of the medication occurred. Currently, after
eighteen months of treatment, the patient is still in remission. The inflammatory
parameters are not elevated and fever is absent. Upon re-evaluation on CT scan, there
were only minor residual vessel wall derangements visible at the site of the former
aneurysms. The follow-up of the pulmonary hypertension was done indirectly by cardiac
ultrasonography and showed no increase of pulmonary hypertension. Sildenafil and bosentan
are continued. The papilledema had resolved, cerebral imaging was not repeated.

Discussion

We present a case of recurrent hemoptysis and pulmonary hypertension in an 11-year-old
boy. The symptoms of the patient appeared to be the result of an inflammatory destructive
process solely affecting the medium sized pulmonary and bronchial vessels. However,
the involvement of both pulmonary and systemic vessels makes classification of the
disease difficult.

The vasculitis of medium-sized vessels described in this report might be classified
as PAN because the patient met the full diagnostic criteria of childhood PAN, that
include: angiographic or histologic abnormalities combined with myalgia, and symptoms
suggesting involvement of a major organ system [1].

PAN is a vasculitis typically involving medium sized vessels and the disease is rare
in childhood with an incidence of < 1 in 1 million [9]. PAN most commonly involves skin, joints, peripheral nerves, gastrointestinal tract
and kidney, and disease manifestations are diverse. Pulmonary involvement is rare
but was described to occur in ~11% of juvenile systemic PAN cases [10]. In the same study, 8 out of 56 (14%) juvenile PAN patients had aneurysms in central
nervous system arteries. Pulmonary involvement in PAN includes arteritis of bronchial
arteries, but diffuse alveolar damage and interstitial fibrosis have also been detected
in autopsy cases [11]. The risk of venous thrombosis in PAN is higher compared to the general population
[12,13], which may be attributable to the systemic inflammation. In the presented case, all
prothrombotic factors examined (lupus anticoagulant, anti-cardiolipins) were negative.
To our knowledge, the incidence of venous sinus thrombosis in PAN has not been studied.

HSS is characterized by multiple bilateral pulmonary artery aneurysms and venous thrombosis
[5,7,14]. Hughes and Stovin described this syndrome for the first time in 1959. To our knowledge,
only four pediatric cases have been described, aged 12, 14 (twice) and 16 (Table 1) [14,15]. The pathogenesis of this disease remains speculative, and previously it has been
suggested that HSS is an incomplete variant of BD based on the occurrence of pulmonary
vasculitis and venous thrombosis in both disease entities [5,7]. Review of adult and pediatric cases showed that no history of oral ulcers has been
described in the context of HSS. That is mandatory for the diagnosis of BD as the
diagnostic criteria include oral ulcers combined with two of the following symptoms:
genital ulcers, ocular lesions, skin lesions, positive pathergy test (Table 1) [4,6,16].

We argue, given the symptoms described in the current and previous case reports, that
it is more likely that HSS is a variant of PAN rather than BD. This would apply to
children and adults, as the diagnostic criteria do not differ in this respect. The
presented case fulfills the diagnostic criteria with angiographic abnormalities of
medium-sized vessels, and myalgia. In other published HSS cases, the presence or absence
of mylagia or one of the other minor criteria for the diagnosis of PAN, are not mentioned.
The therapeutic approach to HSS is similar to that of PAN, as both respond well to
cyclophosphamide courses [17]. Our case illustrates the beneficial effect of a treatment regimen entailing a combination
of high-dose steroids and cyclophosphamide pulses.

Conclusions

In summary, we present a case of isolated pulmonary vasculitis with involvement of
both the pulmonary and bronchial vessels and concomitant dural venous sinus thrombosis
in an 11-year-old boy. The presentation of pulmonary vasculitis with lymphadenopathy,
fever, weight loss, and hemoptysis as presented in this report has a broad differential
diagnosis, including infections, malignancies and inflammatory disease. This may well
represent a case of HSS. Based on our findings and previous case reports we argue
that HSS might be a disease closely related to PAN. We cannot support this speculation
with histological findings, since it was impossible to obtain histology in the presented
patient. Treatment with high-dose steroids and cyclophosphamide induced remission
and thus might be an effective therapeutic regimen in (pediatric) cases of HSS.

Consent

Written informed consent was obtained from the patient's parents for publication of
this case report and any accompanying images. A copy of the written consent is available
for review by the Editor-in-Chief of this journal

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

WdV, GK, MR, HB, ML, WA contributed to the diagnostic work-up and treatment of the
patient. WdV, GK, MR and WA have been involved in drafting the manuscript. All authors
read and approved the final manuscript.